Extended infusion of β-lactams significantly reduces mortality and enhances microbiological eradication in paediatric patients: a systematic review and meta-analysis

Summary Background Paediatric patients are often exposed to subtherapeutic levels or treatment failure of β-lactams, and prolonged infusion may be beneficial. We aimed to investigate the efficacy and safety of extended infusion (EI; defined as ≥3 h) or continuous infusion vs. short, intermittent infusion (SI; defined as ≤60 min) of β-lactams in patients <21 years of age. Methods A systematic review and meta-analysis was conducted to compare EI and continuous infusion with SI of β-lactams in children. A systematic search was performed in MEDLINE (via PubMed), Embase, CENTRAL, and Scopus databases for randomised controlled trials (RCTs) and observational studies published from database inception up to August 22, 2023. Any comparative study concerned with mortality, clinical efficacy, adverse events, or plasma concentrations of β-lactams for any infection was eligible. Case reports, case series, and patients aged >21 years were excluded. Odds ratios (OR) and median differences with 95% confidence intervals (CI) were calculated using a random-effects model. Risk of bias (ROB) was assessed using ROB2 and ROBINS-I tools. The protocol was registered with PROSPERO, CRD42022375397. Findings In total, 19,980 articles were screened, out of which 19 studies (4195 patients) were included in the meta-analysis. EI administration was associated with a significantly lower all-cause mortality in both RCTs and non-RCTs [OR 0.74; CI 0.55–0.99; I2 = 0%; CI 0–58%]. Early microbiological eradication was higher with EI [OR 3.18; CI 2.24–4.51; I2 = 0%; CI 0–90%], but the clinical cure did not differ significantly between the two groups [OR 1.20; CI 0.17–8.71; I2 = 79%; CI 32–93%]. Achieving the optimal plasma level (50–100% fT > MIC) appeared favourable in the EI group compared to the SI. No significant differences were observed in the adverse events. The overall ROB was high because of the small sample sizes and clinically heterogeneous populations. Interpretation Our findings suggest that extended infusion of β-lactams was associated with lower mortality and increased microbiological eradication and was considered safe compared to short-term infusion. Funding None.


Introduction
Parenteral beta-lactams, including penicillins, cephalosporins, carbapenems, and monobactams, are commonly used antibiotics in paediatrics.Various modes of administration are employed: 1) standard, intermittent (SI) or bolus infusion over 30-60 min, 2) extended infusion (EI) over 3-4 h, 3) continuous infusion over 24 h.In order to provide the best care, we must understand which regimen is better.
Furthermore, the misuse of antibiotics is a serious problem in medical practice, it can lead to treatment failure and increasing the risk of developing antibiotic resistance. 1 To prevent antibiotic resistance, it is essential to maintain plasma concentrations in the target range.Beta-lactams are time-dependent antibiotics, and the optimal microbiological response relies on the duration during which the level of unbound drug remains above the minimal inhibitory concentration (MIC): fT > MIC. 2 In critically ill patients, it is recommended to maintain plasma concentrations 1-or 4-fold higher than the MIC throughout the dosing interval (100% fT > 1-4 × MIC). 3 Inadequacy of the standard administration was confirmed by a multicentre pharmacokinetic pointprevalence study: only 127 of 361 (35.2%) critically ill adult patients achieved 100% fT > 4 × MIC target receiving one beta-lactam antibiotic. 4Subtherapeutic concentrations were measured in 117 of 157 (74.5%) patients treated with SI of amoxicillin-clavulanic acid, piperacillin-tazobactam, and meropenem in a paediatric intensive care unit (PICU).Using the pharmacokinetic/ pharmacodynamic (PK/PD) target of 100% fT > 4 × MIC, only 12 of 157 (7.6%) patients achieved the required level. 5A decreased probability of target attainment was observed in several PK studies in critically ill populations for various antibiotics with standard dosages, and the benefits of prolonged infusion were described. 6,7 is strongly suggested in adults due to the probable clinical advantages.A meta-analysis of randomised controlled trials (RCTs) demonstrated that EI of antipseudomonal beta-lactams for treating sepsis was resulted in significantly lower mortality than SI. 8 Furthermore, all-cause mortality was lower in critically ill adult patients with predominant respiratory infections who received EI than in those who received SI. 9 Based on this, we may assume that paediatric patients, especially critically ill patients, are similarly affected by inappropriate dosing and that EI might be similarly beneficial for them.Our aim, therefore, was to investigate the clinical efficacy and safety of EI for betalactams in children.

Search strategy and selection criteria
The recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, 10 and the Cochrane Handbook 11 were followed.The study protocol was registered in the PROSPERO database (CRD42022375397).We conducted minor changes: infection-related mortality was examined because it can represent the real effectiveness of the administered drug; and patients were under the age of 18 instead of 21 years in the included articles, because studies with a population between age of 18 and 21 years were not identified.
The PICO framework 12 was used to answer the clinical question.Studies reporting on (P) paediatric patients (0-21 years) treated with beta-lactam antibiotics

Research in context
Evidence before this study Meta-analyses among adults and pharmacokinetic studies and reviews among paediatric patients support the hypothesis that extended or continuous infusion of beta-lactams can be more efficacious than the standard intermittent infusion.A literature search of four databases (MEDLINE via PubMed, Embase, CENTRAL, and Scopus) was performed on the 22nd of August 2023.No language or other restrictions were applied.The search key contained one paediatric, two dosing, and one antibiotic domain.Patients under the age of 21 years were included, and comparative studies were eligible that contained information regarding mortality, clinical efficacy, adverse events, or plasma concentrations of β-lactams.The overall risk of bias was high because of the small number of studies and complex composition of the study population, characterised by diverse age groups and comorbid conditions.

Added value of this study
This is the first comprehensive meta-analysis investigating the clinical efficacy and safety of extended infusion of β-lactams in paediatric patients.Our study provides data that extended infusion of beta-lactams showed significantly lower all-cause mortality and earlier microbiological eradication than shortterm infusion, and it was associated with a lower infectionrelated mortality rate in children.Furthermore, there was no significant difference in adverse events.The study not only reported statistical significance but also considered clinical relevance, which is crucial for translating research findings into clinical practice.Our findings encourage further prospective data collection of extended infusion especially among neonates and critically ill children due to the limitations and low evidence level.

Implications of all the available evidence
Considering extended or continuous infusion of beta-lactams, particularly for neonates and critically ill children, as well as for patients receiving meropenem, is advisable.The implementation of therapeutic drug monitoring is essential.To gain a more precise understanding of the issue at hand, further prospective data collection through comparative clinical trials, along with the measurement of plasma concentrations, is warranted.
were included.In the intervention group (I), prolonged, extended, or continuous infusion was administered; the comparator group (C) received short-term and intermittent infusions.In the following, we refer to EI and continuous infusion collectively as extended.The primary outcomes (O) were all-cause, short-term intrahospital mortality, and infection-related mortality.As secondary outcomes, we evaluated the rate of clinical cure or treatment failure, success of microbiological eradication, appearance of adverse events, achievement of PK/PD targets based on drug levels, and length of hospital stay (LOS).RCTs, non-randomized observational studies (non-RCTs) were included in the analysis.Adult patients (>21 years of age), case reports, and case series were excluded.
Our systematic search was conducted on the 27th of November 2022, and an updated search on the 22nd of August 2023, using four medical databases (MEDLINE via PubMed, Embase, CENTRAL, and Scopus).In addition, the references of the included studies were searched.
During the systematic search, the search key contained four domains without language restrictions or filtering options: one paediatric, two dosing, and one antibiotic domain.The full search key is provided in Supplementary Material (Supplementary Table 1S).
The search results were exported to EndNote 20 citation manager (Clarivate Analytics, Philadelphia, PA, USA).After automatic and manual duplicate removal (KAB), articles were selected using the Rayyan Intelligent Systematic Review program.The selection was performed by two independent review authors (KAB and ÁET) by title, abstract, and full text according to the inclusion criteria.Disagreements were resolved with the corresponding author's involvement.Cohen's Kappa coefficient was calculated at each selection step to evaluate the level of agreement.

Data analysis
From the eligible articles, patient-level data were independently collected by two authors (KAB and ÁET) using a standardized data collection sheet.
The following data were extracted: study characteristics (first author, year of publication, study design, study period, country, number of centres, name of drugs), population description and demographics (sample size, percentage of female participants, age, indication of the antibiotic(s), patients with positive microbiological culture, patients with co-administered antibiotics), therapy details (drug type, dose, regimen, length of infusion, duration), and outcomes as reported in each article.Microsoft Excel (Microsoft, Office 365, Redmond, WA, USA) was used for data collection.
Two authors (KAB, ÁET) independently performed the risk of bias assessment using the RoB2 risk-of-bias tool in the case of RCTs and the ROBINS-I tool in the case of non-RCTs.A consensus was reached by involving the corresponding author.The domains evaluated were bias arising from the randomisation process (RCTs), bias due to confounding (non-RCTs), selection of participants (non-RCTs), classification of intervention (non-RCTs), deviations from the intended intervention (both), missing data (both), the measurement of the outcomes (both), and the selection of the reported results (both).The conclusion of the risk assessment was characterized as 'low', 'moderate' and 'serious'.
Grading of Recommendations Assessment, Development and Evaluation (GRADE) 13 approach was followed to evaluate the quality of evidence of our results, and the GRADEpro tool (software; McMaster University and Evidence Prime, 2022.Available from gradepro.org)was used based on the recommendations of the Cochrane Collaboration.Each outcome was rated for the risk of bias, inconsistency, indirectness, imprecision, publication bias, and the presence of a large effect, dosedependent response.Plausible confounders were rated as 'not serious', 'serious', or 'very serious'.The final certainty of evidence was categorised as 'very low', 'low', 'moderate', or 'high'.
Considering the study heterogeneity, a randomeffects model was used to pool effect sizes.Odds ratios (OR) and risk ratios (RR) with 95% confidence intervals (CIs) were calculated for dichotomous outcomes extracted based on the numbers of patients and events extracted from the studies.The results are presented as the odds or risk of an event in the extended group divided by the odds or risk of the same event in the bolus group.Pooled risk ratios were calculated for all-cause mortality if all meta-analysed studies were RCTs.
For continuous outcomes (LOS, PICU length of stay, and duration of antibiotic course), quartiles were given in most cases (instead of mean and standard deviation).The difference between the group medians was used as an effect size measure with 95% CI. 14 Median values of the bolus group were subtracted from those of the extended group.
The results were considered statistically significant if the pooled CI did not contain the null value, and p-value was less than 0.05.We summarised the findings related to the meta-analysis on forest plots.If the study number was sufficiently large and not too heterogeneous, we reported the prediction intervals (i.e., the expected range of effects of future studies) of the results where applicable.Between-study heterogeneity was described using Higgins and Thompson's I 2 statistics. 15mall study publication bias was assessed by visual inspection of funnel plots.Potential outlier publications were explored by using different influence measures and plots. 16ll statistical analyses were calculated by R software 17 using the meta 18 package for OR meta-analysis calculations and plots, the metamedian 19 package for difference of median meta-analysis calculations, and the dmetar 20 package for additional influential analysis calculations and plots.
A subgroup analysis was performed on all-cause mortality (RCTs and non-RCTs), infection-related mortality (non-RCTs), and acute kidney injury (neonates and patients with cystic fibrosis [CF]).We analysed the allcause mortality of neonates and meropenem-treated patients separately.
Additional details on calculations, data synthesis, publication bias assessment, and influential analyses, are included in the Supplementary Material (pages 3-4).

Role of the funding source
There was no funding source for this study.The corresponding author and KAB had access to all the data and had responsibility for the decision to submit the study for publication.

Search and selection
In total, 19,980 studies were identified and screened.After duplicate removal, and title and abstract selection (Cohen's Kappa 0.88), we found 34 eligible articles during the full-text article analysis (Cohen's Kappa 0.87).Three other eligible articles were identified through citation checking.One additional Chinese study 21 was selected from a systematic review 7 and extracted with XL's help.Nineteen of 38 articles were excluded from the meta-analysis because of overlapping populations (6), no comparator (6), or their outcomes could not be pooled with others (7).][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] One of them was a trial protocol 26 and one of them was poster abstract. 30Two studies were bicentric, 26,35 the others were single centre.The studies included patients under 18 years of age.The selection process is summarised in Fig. 1.The excluded studies at full-text screening stage are listed in Supplementary Table 2S.

Decrease in mortality
Seven RCTs and five non-RCTs that reported all-cause mortality within 30 days from the beginning of treatment or in-hospital mortality were included.Separate analyses are in the Supplementary Material (Supplementary Figures 1aS and bS and 2S).Overall, EI was associated with a significantly lower mortality than SI [11.8% vs. 13.8%;OR 0.74; CI 0.55-0.99;I 2 = 0%; CI 0-58%].Non-RCTs showed a significant effect, and RCTs had the similar, but non-significant tendency.With the two meningitis studies 28,29 omitted because of the different routes of administration and extremely severe conditions, clinically relevant but statistically insignificant results were obtained [4.62% vs. 7.17%; OR 0.62; CI 0.37-1.05;I 2 = 0%; CI 0-62%] (Fig. 2a and b).The population was mixed, but statistically not heterogeneous.Funnel plots, influential analyses and leave-one-out plots are in the Supplementary Material (Supplementary Figures 7S-9S).No sign for publication bias was observed.Two articles 26,29 as potential influentials are detected, although their influential effect is mainly due to the large number of participants.The change in effect size would be not clinically meaningful by omitting Pelkonen et al., 29 but it would be by omitting Fuentes et al. 26 (after omitting the two meningitis studies 28,29 ).
In meropenem-treated patients, mortality in the SI group was significantly (three times) higher than in the EI group [OR 0.31; CI 0.13-0.73].In the neonatal subset, the result was similar, but non-significant [OR 0.34; CI 0.08-1.40].However, the study and sample sizes were small (Fig. 3a and b).

Secondary outcomes No change in clinical cure
The clinical cure reported complete symptomatic resolution of clinical signs (absence of fever, white blood cell count normalisation, negative follow-up cultures, hemodynamic stability, normal arterial blood gas test values, temperature stability, tolerance for enteral feeding, and discontinuation of inotropes for at least 48h; CF patients within 5% of baseline ppFEV1 [percent predicted forced expiratory volume] at discharge) related to the infection at the end of therapy or at discharge.No significant difference was found between the two groups [OR 1.20; CI 0.17-8.71;I 2 = 79%; CI 32-93%].The sample sizes were small, and the groups were heterogeneous (Fig. 4a).Treatment failure on the third day did not differ significantly between the two groups [OR 0.84; CI 0.34-2.05](Supplementary Figure 3S).
Higher optimal exposure (50-100% fT > 4 × MIC) could not be evaluated, but according to two studies, 3,22 EI might be more likely to reach it.In one study, 80 PICU patients received 106 β-lactam courses, and CI provided more optimal PK target (100% fT > 4 × MIC) than SI (n = 22/32, 69% for CI vs. n = 35/74, 47% for SI), together with less underexposure and more overexposure. 40Comparing the trough levels of meropenem and piperacillin in paediatric haematology-oncology patients, only 8% of piperacillin levels given continuously were insufficient (out of the range of 30-60 mg/L); however, 67% of SI plasma concentrations showed underexposure (lower than the targets: meropenem 2-8 mg/L, piperacillin 8-30 mg/L). 39In a retrospective study more samples reached the target concentration with continuous infusion than with SI (62.2% vs. 38.4%,p < 0.001), and less sample were over-or underdosed, but the target was not defined. 43 study among critically ill children (21 patients, 46 measurements) treated with continuous infusion of beta-lactams showed that the optimal target (100% fT > 4 × MIC) was achieved in 76.2% of cases. 41Among 11 neonates receiving amoxicillin continuously, only 3 of 22 samples did not reach the PK index of 100% fT > 4 × MIC of Escherichia coli. 44 difference in acute kidney injury (AKI) AKI was defined as either an elevated creatinine level or by using KDIGO guidelines.These studies included neonates and children with CF.Alterations in AKI events were not statistically significant [OR 0.90; CI 0.42-1.89;I 2 = 37%; CI 0-75%] (Fig. 6a).There was also no statistically significant difference between CF patients and neonates [OR 0.90; CI 0.42-1.89](Supplementary Figure 4S).

No difference in hepatic adverse events
Hepatic adverse events included any abnormalities in transaminase levels, and regarding study by Riggsbee et al. we chose ALT levels to identify hepatotoxicity. 38imilarly to AKI, there was no statistically significant difference between the two groups [OR 1.11; CI 0.77-1.58;I 2 = 0%; CI 0-79%] (Fig. 6b).Both types of administrations were considered safe.However, the investigation of all adverse events was difficult, and the interpretation can be problematic because of the paucity  and variability of the definitions (Supplementary Figure 5S).
No difference in LOS, PICU length of stay and duration of the antibiotic LOS, PICU length of stay, and duration of antibiotic course were expressed in days.No significant differences were found [LOS: OR 0.90; CI 0.52-2.32](Supplementary Figure 6S).

Risk of bias assessment
The overall risk of bias was low among RCTs.However, we assessed some concerns in the study by Chongcharoenyanon et al. 22 due to baseline differences between intervention groups, missing data, and selection of the reported result, and in the study by Wang et al. 21ue to the selection of the reported result.The overall risk of bias was high among non-RCTs, mainly due to confounding factors, inaccurate selection of participants, and missing data.The quality of evidence ranged between very low to moderate because of the small sample size, overall high risk of bias, and clinically heterogeneous populations.The summary figures of the risk of bias assessment and the summary of the findings table for GRADE are provided in the Supplementary Material (Supplementary Figures 10S and 11S and Supplementary Table 5S).

Discussion
Overall, patients died approximately 26% lower odds [CI 0.55; 0.9] in the EI group than in the SI group.The total mortality of the studies ranged 0-35.8% and was very high among patients with meningitis (>35%). 28,29revious meta-analyses of adults have shown the advantages of EI in sepsis and respiratory infections. 8,9,45n a meta-analysis of RCTs, a non-significant association was found between EI and lower mortality; however, one study showed the advantage of EI with ceftazidime in critically ill adults with severe infections (EI: 3/10, SI: 9/11 deaths). 46In a study among critical care paediatric patients, those who received EI had a lower all-cause mortality rate within 30 days of completing antibiotics compared to SI (2.1% vs. 19.6%;p = 0.006). 32Mortality is influenced by comorbidities, the presence of immune deficiency, the need for respiratory support, and the need for inotropic therapy.The Acute Physiology and Chronic Health Evaluation (APACHE) II score (ranging 0-71) is a severity index with higher scores indicating an increased risk of death.In an analysis of individual patient data, mortality rates were slightly lower in the continuous infusion group for patients with an APACHE II score of ≥22 [RR 0.74; 95% CI 0.53-1.01],but not for those with a score <22 [RR 0.69; 95% CI 0.39-1.21]. 47EI may offer greater benefit for critically ill patients with severe infections.
The subset analysis of all-cause mortality among meropenem-treated patients found similar results to those of previous meta-analyses in a severely ill population: fatalities in the EI group were significantly lower than those in the SI group. 48,49In the literature, no significant differences have been found between betalactam subclasses. 8,45,46he occurrence of proven bacteraemia is low or unknown, and the relevance of all-cause mortality is debatable. 25Examining infection-related mortality, deaths occurred nearly 50% less likely in the EI group, which is a clinically relevant, but not significant result [CI 0.24; 1.12].An adult RCT reported ventilatorassociated pneumonia (VAP)-related mortality, and the extended group (amikacin + EI meropenem + nebulized amikacin; 4/30) was associated with lower mortality than the control group (amikacin + SI meropenem 8/ 30). 50However, the additional nebulized antibiotic might have also contributed to the reduction.
In contrast to mortality, no differences were found in clinical cure or treatment failure.However, two neonatal studies have shown the clinical effectiveness of EI. 33,34 In another newborn study, the duration of clinical symptoms remission was shorter in the extended group (3.1 ± 1.8 days vs. 6.2 ± 1.6 days, p = 0.036). 21The EI of meropenem may be beneficial for late-onset neonatal sepsis.In previous meta-analyses, meropenem EI had a significantly higher cure rate than SI. 48,496][47] EI was preferred for more seriously ill patients with pneumonia; the clinical cure rate was higher in patients with APACHE II scores ≥15 receiving EI vs. SI. 45icrobiological eradication was the most objective measure of efficacy.Only three meropenem studies have reported pathogenic culture data, demonstrating the effectiveness of EI. 51 Two meta-analyses that administered meropenem in severe infections showed a significantly higher bacterial eradication rate in the EI group. 48,49ppropriate plasma concentrations are crucial for eradication.Critically ill children may be exposed to insufficient antibiotic levels due to alterations in PK properties (such as elevated glomerular filtration rate), fluid shifts, systematic inflammation response and treatment with vasoactive agents. 5,6According to a study carried out in a PICU, augmented renal clearance (ARC, creatinine clearance CrCl ≥130 mL/min/1.73m 2 ) was present for at least one day in 62 of 92 (67.4%) patients. 52he level of antimicrobial exposure was inadequate in 85% of patients with ARC in an included study. 39lasma meropenem concentrations were lower in patients with ARC than without ARC in another study. 24ased on paediatric PK studies, which employed Monte Carlo simulations to determine the effects of modifying components of an antimicrobial drug  regimen, EI improved the exposure compared to SI. 2 However, plasma concentration measurements were limited to only seven comparative studies, 3,22,24,35,39,40,43 and only three could be included in the meta-analysis.Therapeutic drug monitoring (TDM)-guided dosing enhanced the clinical and microbiological cure and treatment response in critically ill adults but did not affect the mortality.The inclusion of non-septic patients could distort the mortality data. 51Similarly, we also included patients with suspected infection without detection of bacteria.Patients with optimal target (100% Ft > 4 × MIC) had both a significantly higher microbiological eradication rate and lower resistance development rate than underexposed patients in a study. 41wever, we could not evaluate the association between the target achievement and the efficacy.
No serious adverse events were reported, and there was no difference in AKI and hepatotoxicity between the groups, which was consistent with previous adult experiences. 8,45,46,48Concerning cost effectiveness no difference is expected due to the same daily dose and the non-significant difference in the length of stay and duration of the antibiotic course.
Technical issues such as intravenous (IV) access concerns, IV compatibility and antibiotic stability are important in the implementation of extended or continuous infusion in practice.In a study EI was initiated in 143 patients, and the infusion time was   changed only in 11 patients.In 6 cases there were IV access issues (incompatibility/not enough access, preventive change, patient freedom, fear of precipitation). 27hen changing the infusion, stability must be considered, for example meropenem is stable for 3 h after dissolution in room temperature according to the monographs, and continuous infusion can be problematic.
Regarding the strengths of our study, we followed our protocol (only infection-related mortality was an additional outcome), which was registered in PROS-PERO in advance.Rigorous methodology was applied.
Our meta-analysis has several limitations.First, a small number of cases were enrolled in some outcomes, and RCTs and observational cohorts were analysed together.Second, wide range of patients were involved according to age and comorbidities.Third, the posology differed depending on whether a bolus infusion was administered before the first prolonged infusion.Fourth, in some cases, the pathogen was only suspected, or microbiological culture data were not available.Fifth, concomitant antibiotics were used in 10 studies, or sometimes were not reported.Sixth, the follow-up duration was inconsistent in the cases of mortality.Seventh, the definitions of clinical cure differed among studies, and the assessment was subjective.Eighth, there were missing data in TDM, target attainment and microbiological eradication.Ninth, creatinine abnormalities might not directly translate to kidney injury, and this number can be overestimated in preterm neonates.Tenth, the non-RCTs had a high risk of bias.Eleventh, publication bias could not be assessed correctly because of the small number of included studies.
Based on our results, extended or continuous infusion of beta-lactams should be considered, especially for neonates and critically ill children, and among meropenem-treated patients.Therapeutic drug monitoring is necessary.
Further prospective data collection (comparative clinical trials) with plasma concentration measurements is needed to assess the problem in question more accurately. 53n conclusion, extended infusion of beta-lactams showed a significantly lower all-cause mortality rate and earlier microbiological eradication in children.No

Fig. 2 :
Fig. 2: Forest plots of mortality among paediatric patients treated with extended vs. bolus infusion of beta-lactams.(a) All studies (b) without meningitis studies.

Fig. 3 :
Fig. 3: Forest plots of mortality among (a) meropenem treated paediatric patients (b) neonates treated in neonatal intensive care unit (NICU) and (c) infection-related mortality among paediatric patient with a confirmed multidrug-resistant Gram-negative bacteremia (MDR-GNB).

Fig. 4 :
Fig. 4: (a) Forest plot of clinical cure, (b) forest plot of microbiological eradication among paediatric patients treated with extended vs. bolus infusion of beta-lactams.

Fig. 6 :
Fig. 6: Forest plots of adverse events among paediatric patients treated with extended vs. bolus infusion of beta-lactams (a) acute kidney injury (b) hepatic adverse events.

Table 1 :
Baseline characteristics of the included trials in the meta-analysis except neonatal studies.

Table 2 :
CKRT, continuous kidney replacement therapy; ECMO, extracorporeal membrane oxygenation; EI, extended infusion; h, hours; IQR, interquartile range; LOS, length of hospital stay; MIC, minimal inhibitory concentration; NA, not reported or not applicable; PNA, postnatal age; RCT, randomised controlled trial; SD, standard deviation; SI, short-term intermittent infusion.Baseline characteristics of the included neonatal studies in the meta-analysis.
a Data expressed as median [interquartile range].

Table 3 :
Baseline characteristics of the included studies in the systematic review.

Table 4 :
Summary of the applied beta-lactam therapies in the studies included in the meta-analysis.